In chemotherapy of cancer, a number of pharmaceutical agents that inhibit DNA synthesis or that directly inhibit cell division have been used. These pharmaceutical agents function as cytotoxicity, and sometimes prove effective against rapidly dividing cancer cells. In many cases, however, since the cytotoxicity is not limited to cancer cells, they exhibit strong toxicity in normal cells as well. As the current situation stands, therefore, side effects have become a problem in chemotherapy using such pharmaceutical agents. As a different approach acting on a mechanism other than the one mentioned above, a method enhancing the selectivity to suppress growth of cancer cells is known.
Tyrosine kinase is an enzyme that phosphorylates tyrosine residue in proteins. It is widely known that tyrosine kinase plays an important and central role in differentiation and proliferation of cells and in an intracellular signal transduction system. Furthermore, it is also considered that a failure to control tyrosine kinase activity causes aberration in differentiation or proliferation of cells and in an intracellular signal transduction system, thereby directly causing the onset of many diseases. For example, tyrosine kinase activity has been found to be detected more often in arteriosclerosis [Am. J. Physiol., 1991, 260 (4-part 1), C721-C730; Biochem. Biophys. Res. Commun., 1993, 192(3), 1319-1326. etc.] and psoriasis [J. Invest. Deruatol., 1990, 95, 75-95], as well as in tumor cells than in normal cells [Cell, 1987, 50, 823]. Particularly, it has been clarified that growth factor receptor tyrosine kinases (hereinafter to be referred to as receptor tyrosine kinase) such as HER2 (also called ErbB2 or Neu), EGF receptor and the like are deeply involved in the formation of malignant tumor, and that receptor tyrosine kinase activity is potentiated in human cancer [Cancer Res., 1991, 51, 4430-4435; Cancer Res., 1992, 52, 3636-3641; Cancer Chemother. Pharmacol., 1993, 32, 1-19 and the like]. Moreover, these receptor tyrosine kinases have been shown to excessively express in many tumors such as those in brain, lung, stomach, colorectum, pancreas, head and neck portion, esophagus, bladder, kidney, prostate, ovary, breast, uterus, thyroid gland and the like [Med. Bull., 1991, 47, 87; Expert. Opin. Invest. Drugs, 1994, 3 (6), 577-595; JP-A-5-208911]. In addition, involvement of EGF receptors in angiogenesis, which is closely related to metastasis of cancer, has been indicated [J. Biol. Chem., 1995, 912, 895-898; Cancer Res., 1995, 55, 3772-3776]. Accordingly, a pharmaceutical agent that inhibits tyrosine kinase is considered to be useful not only as an agent for the prophylaxis or treatment of the above-mentioned diseases but also as an anticancer agent having a new mechanism, which is applicable to many kinds of cancers and which causes fewer side effects. Various tyrosine kinase inhibitors have been heretofore studied, and disclosed in JP-A-6-73025, JP-A-5-208911, Japanese Patent No. 2994165, JP-T-Hei 12-508657 and a recent paper by Diane H. Boschelli [Drugs of the Future 1999 24(5), 515-537], but have not been put to practical use.
The four receptors of EGF receptor, HER2, ErbB3 and ErbB4 all belong to the ErbB family, and these receptors form a heterocomplex and show interaction in the intracellular signal transduction [J. Clin. Oncol. 2001 19(18s), 32s-40s]. For example, it is known that coexpression of EGF receptor and HER2 accelerates tumorigenesis solely derived from the EGF receptor [Cell 1987 58, 287-292]. There is a report that the coexpression of EGF receptor and HER2 in breast cancer, oral cancer, lung cancer and the like causes poor prognosis [Clin. Cancer Res. 1999 5, 4164-4174]. Furthermore, there is a report that the coexpression of EGF receptor and HER2 in breast cancer relates to the resistance to endocrine therapy [J. Steroid Biochem. 1989 34, 123-131].
The present invention aims at finding a pharmaceutical agent that inhibits EGF receptor tyrosine kinase and a pharmaceutical agent that inhibits both the EGF receptor tyrosine kinase and HER2 tyrosine kinase. The dual inhibitor of EGF receptor and HER2 is advantageous in that it: can be applied to a wider range of diseases and is superior in that the synergistic dual inhibitory action affords a stronger treatment effect as compared to a pharmaceutical agent acting only on a single kinase.
The compound of the present invention shows a sustained enzyme inhibitory action and provides a more superior treatment effect than do conventionally reported reversible inhibitors.